Anti-thrombogenic medical devices and methods

ABSTRACT

Methods for forming an expandable tubular body having a plurality of braided filaments including a first filament including platinum or platinum alloy and a second filament including cobalt-chromium alloy. The methods include applying a first phosphorylcholine material directly on the platinum or platinum alloy of the first filament and applying a silane material on the second filament followed by a second phosphorylcholine material on the silane material on the second filament. The first and second phosphorylcholine materials each define a thickness of less than 100 nanometers.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/173,879 filed on Oct. 29, 2018, which is a continuation of U.S.patent application Ser. No. 15/584,077 filed on May 2, 2017, now U.S.Pat. No. 10,258,486, which is a continuation of U.S. patent applicationSer. No. 14/087,459 filed on Nov. 22, 2013, now U.S. Pat. No. 9,668,890,each of which is incorporated herein by reference in its entirety.

BACKGROUND

Walls of the vasculature, particularly arterial walls, may develop areasof weakness and/or dilatation called aneurysms. The rupture of certainaneurysms, for example abdominal aortic aneurysms and brain or cerebralaneurysms in the neurovasculature, can cause hemorrhage and death.Aneurysms are generally treated by excluding the weakened part of thevessel from the arterial circulation. For treating a cerebral aneurysm,such exclusion may be accomplished by: (i) surgical clipping, where ametal clip is secured around the base of the aneurysm; (ii) packing theaneurysm with small, flexible wire coils (micro-coils); (iii) usingembolic materials to “fill” an aneurysm; (iv) using detachable balloonsor coils to occlude the parent vessel that supplies the aneurysm; and/or(v) intravascular stenting, including flow-diverter therapy.

Stents include generally tubular prostheses that expand radially orotherwise within a vessel or lumen to provide therapy or support againstblockage of the vessel. Stents of various construction may be utilized,including balloon expandable metal stents, self-expanding braided metalstents, knitted metal stents, coiled stents, rolled stents, and thelike. Stent-grafts are also used, which include a tubular graft materialsupported by a metallic stent.

Coatings have been applied to medical devices to impart lubriciousand/or anti-adhesive properties and serve as depots for bioactive agentrelease. As medical devices, especially those possessing irregularand/or rough surfaces, may be conducive to thrombus formation, coatingsmay be applied to these medical devices to reduce the formation ofthrombi. Adherence of these coatings to the substrate used to form thedevice may prove difficult, with delamination occurring in some cases.

SUMMARY

In accordance with certain embodiments in the present disclosure, amedical device (e.g., a stent) is provided having outer layer(s) thereonthat provide the device with reduced thrombogenicity. In embodiments, amedical device of the present disclosure includes an expandable tubularbody having a plurality of braided filaments configured to be implantedin a blood vessel, the braided filaments including a metal such asplatinum, cobalt, chromium, nickel, alloys thereof, and combinationsthereof; wherein the filaments have an outer surface including aphosphorylcholine; and wherein the phosphorylcholine has a thickness ofless than 100 nanometers.

Systems using the medical devices of the present disclosure are alsoprovided. In embodiments, a system of the present disclosure includes asystem for treating an aneurysm. Such a system includes a core assemblyconfigured for insertion into a blood vessel, the core assembly having adistal segment; an expandable tubular body carried by the core assemblydistal segment, the tubular body having a plurality of braided filamentsconfigured to be implanted in a blood vessel, the braided filamentsincluding a metal such as platinum, cobalt, chromium, nickel, alloysthereof, and combinations thereof; wherein the filaments have an outersurface including a phosphorylcholine; and wherein the phosphorylcholinehas a thickness of less than 100 nanometers.

Methods for treating medical conditions with the devices of the presentdisclosure are also provided. In embodiments, a method of the presentdisclosure includes a method of treating an aneurysm formed in a wall ofa parent blood vessel. Such a method includes deploying the tubular bodyof a medical device of the present disclosure into the parent bloodvessel so that a sidewall of the medical device extends across a neck ofthe aneurysm, thereby causing thrombosis within the aneurysm.

In other embodiments, a method of treating an aneurysm formed in a wallof a parent blood vessel of a patient includes deploying aflow-diverting metallic stent having a phosphorylcholine outer surfaceof less than 100 nanometers in thickness in the parent blood vesselacross the neck of the aneurysm, so as to treat the aneurysm; and either(a) prescribing to the patient a reduced protocol of anti-plateletmedication, in comparison to a protocol that would be prescribed to thepatient if an otherwise similar stent that lacks the phosphorylcholineouter surface were deployed in the patient, or (b) declining toprescribe to the patient any anti-platelet medication.

In yet other embodiments, a method of treating an aneurysm formed in awall of a parent blood vessel of a patient includes deploying aflow-diverting stent in the parent blood vessel across the neck of theaneurysm, so as to treat the aneurysm, at least a portion of the stenthaving a phosphorylcholine outer surface of less than 100 nanometers inthickness so that the stent exhibits a peak thrombin concentration thatis less than 0.8 times the peak thrombin concentration of an otherwisesimilar stent that lacks the phosphorylcholine outer surface; and either(a) prescribing to the patient a reduced protocol of anti-plateletmedication, in comparison to a protocol that would be prescribed to thepatient if the otherwise similar stent that lacks the phosphorylcholineouter surface were deployed in the patient, or (b) declining toprescribe to the patient any anti-platelet medication.

The subject technology is illustrated, for example, according to variousaspects described below. Various examples of aspects of the subjecttechnology are described as numbered clauses (1, 2, 3, etc.) forconvenience. These are provided as examples and do not limit the subjecttechnology. It is noted that any of the dependent clauses may becombined in any combination, and placed into a respective independentclause, e.g., clause 1 or clause 5. The other clauses can be presentedin a similar manner.

Clause 1. A medical device, comprising:

-   -   an expandable tubular body comprising a plurality of braided        filaments configured to be implanted in a blood vessel, the        braided filaments comprising a metal selected from the group        consisting of platinum, cobalt, chromium, nickel, alloys        thereof, and combinations thereof;    -   wherein the filaments have an outer surface comprising a        phosphorylcholine; and    -   wherein the phosphorylcholine has a thickness of less than 100        nanometers.

Clause 2. The medical device of Clause 1, wherein the phosphorylcholineis selected from the group consisting of 2-methacryloyloxyethylphosphorylcholine, 2-acryloyloxyethyl phosphorylcholine, andphosphorylcholines based upon monomers such as2-(meth)acryloyloxyethyl-2′-(trimethylammonio)ethyl phosphate,3-(meth)acryloyloxypropyl-2′-(trimethylammonio)ethyl phosphate,4-(meth)acryloyloxybutyl-2′-(trimethylammonio)ethyl phosphate,5-(meth)acryloyloxypentyl-2′-(trimethylammonio)ethyl phosphate,6-(meth)acryloyloxyhexyl-2′-(trimethylammonio)ethyl phosphate,2-(meth)acryloyloxyethyl-2′-(triethylammonio)ethyl phosphate,2-(meth)acryloyloxyethyl-2′-(tripropylammonio)ethyl phosphate,2-(meth)acryloyloxyethyl-2′-(tributylammonio)ethyl phosphate,2-(meth)acryloyloxypropyl-2′-(trimethylammonio)ethyl phosphate,2-(meth)acryloyloxybutyl-2′-(trimethylammonio)ethyl phosphate,2-(meth)acryloyloxypentyl-2′-(trimethylammonio)ethyl phosphate,2-(meth)acryloyloxyhexyl-2′-(trimethylammonio)ethyl phosphate,2-(meth)acryloyloxyethyl-3′-(trimethylammonio)propyl phosphate,3-(meth)acryloyloxypropyl-3′-(trimethylammonio)propyl phosphate,4-(meth)acryloyloxybutyl-3′-(trimethylammonio)propyl phosphate,5-(meth)acryloyloxypentyl-3′-(trimethylammonio)propyl phosphate,6-(meth)acryloyloxyhexyl-3′-(trimethylammonio)propyl phosphate,2-(meth)acryloyloxyethyl-4′-(trimethylammonio)butyl phosphate,3-(meth)acryloyloxypropyl-4′-(trimethylammonio)butyl phosphate,4-(meth)acryloyloxybutyl-4′-(trimethylammonio)butyl phosphate,5-(meth)acryloyloxypentyl-4′-(trimethylammonio)butyl phosphate,6-(meth)acryloyloxyhexyl-4′-(trimethylammonio)butylphosphate, andcombinations thereof.

Clause 3. The medical device of Clause 1, wherein the phosphorylcholinecomprises a copolymer having a reactive chemical group.

Clause 4. The medical device of Clause 3, wherein the reactive chemicalgroup is selected from the group consisting of amine, hydroxyl, epoxy,silane, aldehyde, carboxylate and thiol.

Clause 5. The medical device of Clause 1, further comprising a silanelayer between the metal and the phosphorylcholine.

Clause 6. The medical device of Clause 5, wherein the silane is selectedfrom the group consisting of 3-glycidoxypropyltrimethoxysilane,2-(3,4-epoxycyclohexyl)ethyl-triethoxysilane,2-(3,4-epoxycyclohexyl)ethyl-trimethoxysilane,(3-glycidoxypropyl)trimethoxysilane, (3-glycidoxypropyl)triethoxysilane,5,6-epoxyhexyltriethoxysilane, (3-glycidoxypropyl)methyldiethoxysilane,(3-glycidoxypropyl)methyldimethoxysilane,(3-glycidoxypropyl)dimethylethoxysilane,3-isocyanatopropyltriethoxysilane,(isocyanatomethyl)methyldimethoxysilane,3-isocyanatopropyltrimethoxysilane,tris(3-trimethoxysilylpropyl)isocyanurate,(3-triethoxysilylpropyl)-t-butylcarbamate,triethoxysilylpropylethylcarbamate, 3-thiocyanatopropyltriethoxysilane,and combinations thereof.

Clause 7. The medical device of Clause 1, wherein the tubular bodycomprises (a) platinum or platinum alloy filaments, combined with (b)cobalt-chromium alloy filaments.

Clause 8. The medical device of Clause 7, wherein the platinum orplatinum alloy filaments possess a layer of the phosphorylcholine, andwherein the cobalt-chromium alloy filaments possess a silaneintermediate layer between the cobalt-chromium alloy filaments and thephosphorylcholine.

Clause 9. The medical device of Clause 7, wherein the phosphorylcholine,or a polymer or copolymer thereof, is chemically bonded directly to theplatinum or platinum alloy filaments.

Clause 10. The medical device of Clause 7, wherein thephosphorylcholine, or a polymer or copolymer thereof, is covalentlybonded to the platinum or platinum alloy filaments.

Clause 11. The medical device of Clause 7, wherein thephosphorylcholine, or a polymer or copolymer thereof, is chemicallybonded to a silane over the cobalt-chromium alloy filaments.

Clause 12. The medical device of Clause 11, wherein thephosphorylcholine, or the polymer or copolymer thereof, is covalentlybonded to a silane over the cobalt-chromium alloy filaments.

Clause 13. The medical device of Clause 1, wherein the tubular bodycomprises platinum or platinum alloy filaments.

Clause 14. The medical device of Clause 13, wherein thephosphorylcholine, or a polymer or copolymer thereof, is covalentlybonded to the platinum or platinum alloy filaments.

Clause 15. The medical device of Clause 13, wherein thephosphorylcholine, or a polymer or copolymer thereof, is chemicallybonded to the platinum or platinum alloy filaments.

Clause 16. The medical device of Clause 1, wherein the tubular body hasa sidewall formed by the braided filaments, the sidewall having aplurality of pores therein, the plurality of pores being sized toinhibit flow of blood through the sidewall into an aneurysm to a degreesufficient to lead to thrombosis and healing of the aneurysm when thetubular body is positioned in a blood vessel and adjacent to theaneurysm.

Clause 17. The medical device of Clause 1, wherein the tubular body hasa sidewall formed by the braided filaments, the sidewall having aplurality of pores therein, the plurality of pores having an averagepore size that is less than or equal to 500 microns.

Clause 18. The medical device of Clause 1, wherein the tubular body isheat set so that the filaments are at their least-stressed configurationin the tubular body.

Clause 19. The medical device of Clause 1, wherein the outer surface isan outermost surface of the filaments.

Clause 20. The medical device of Clause 1, wherein the medical devicecomprises a stent.

Clause 21. The medical device of Clause 1, wherein the phosphorylcholinehas a thickness from about 1 to about 100 nanometers.

Clause 22. The medical device of Clause 1, wherein the tubular body isself-expanding.

Clause 23. The medical device of Clause 1, wherein the device is lessthrombogenic than an identical device whose braided filaments areentirely bare metal.

Clause 24. The medical device of Clause 1, wherein the device exhibitsan elapsed time before peak thrombin formation that is at least 1.5times the elapsed time before peak thrombin formation for an identicaldevice whose braided filaments are entirely bare metal.

Clause 25. The medical device of Clause 1, wherein the device exhibits apeak thrombin concentration that is less than 0.8 times the peakthrombin concentration for an identical device whose braided filamentsare entirely bare metal.

Clause 26. A system for treating an aneurysm, the system comprising:

-   -   a core assembly configured for insertion into a blood vessel,        the core assembly having a distal segment;    -   an expandable tubular body carried by the core assembly distal        segment, the tubular body comprising a plurality of braided        filaments configured to be implanted in a blood vessel, the        braided filaments comprising a metal selected from the group        consisting of platinum, cobalt, chromium, nickel, alloys        thereof, and combinations thereof;    -   wherein the filaments have an outer surface comprising a        phosphorylcholine; and    -   wherein the phosphorylcholine has a thickness of less than 100        nanometers.

Clause 27. The system of Clause 26, wherein the phosphorylcholine isselected from the group consisting of 2-methacryloyloxyethylphosphorylcholine, 2-acryloyloxyethyl phosphorylcholine, andphosphorylcholines based upon monomers such as2-(meth)acryloyloxyethyl-2′-(trimethylammonio)ethyl phosphate,3-(meth)acryloyloxypropyl-2′-(trimethylammonio)ethyl phosphate,4-(meth)acryloyloxybutyl-2′-(trimethylammonio)ethyl phosphate,5-(meth)acryloyloxypentyl-2′-(trimethylammonio)ethyl phosphate,6-(meth)acryloyloxyhexyl-2′-(trimethylammonio)ethyl phosphate,2-(meth)acryloyloxyethyl-2′-(triethylammonio)ethyl phosphate,2-(meth)acryloyloxyethyl-2′-(tripropylammonio)ethyl phosphate,2-(meth)acryloyloxyethyl-2′-(tributylammonio)ethyl phosphate,2-(meth)acryloyloxypropyl-2′-(trimethylammonio)ethyl phosphate,2-(meth)acryloyloxybutyl-2′-(trimethylammonio)ethyl phosphate,2-(meth)acryloyloxypentyl-2′-(trimethylammonio)ethyl phosphate,2-(meth)acryloyloxyhexyl-2′-(trimethylammonio)ethyl phosphate,2-(meth)acryloyloxyethyl-3′-(trimethylammonio)propyl phosphate,3-(meth)acryloyloxypropyl-3′-(trimethylammonio)propyl phosphate,4-(meth)acryloyloxybutyl-3′-(trimethylammonio)propyl phosphate,5-(meth)acryloyloxypentyl-3′-(trimethylammonio)propyl phosphate,6-(meth)acryloyloxyhexyl-3′-(trimethylammonio)propyl phosphate,2-(meth)acryloyloxyethyl-4′-(trimethylammonio)butyl phosphate,3-(meth)acryloyloxypropyl-4′-(trimethylammonio)butyl phosphate,4-(meth)acryloyloxybutyl-4′-(trimethylammonio)butyl phosphate,5-(meth)acryloyloxypentyl-4′-(trimethylammonio)butyl phosphate,6-(meth)acryloyloxyhexyl-4′-(trimethylammonio)butylphosphate, andcombinations thereof.

Clause 28. The system of Clause 26, further comprising a silane layerbetween the metal and the phosphorylcholine.

Clause 29. The system of Clause 28, wherein the silane is selected fromthe group consisting of 3-glycidoxypropyltrimethoxysilane,2-(3,4-epoxycyclohexyl)ethyl-triethoxysilane,2-(3,4-epoxycyclohexyl)ethyl-trimethoxysilane,(3-glycidoxypropyl)trimethoxysilane, (3-glycidoxypropyl)triethoxysilane,5,6-epoxyhexyltriethoxysilane, (3-glycidoxypropyl)methyldiethoxysilane,(3-glycidoxypropyl)methyldimethoxysilane,(3-glycidoxypropyl)dimethylethoxysilane,3-isocyanatopropyltriethoxysilane,(isocyanatomethyl)methyldimethoxysilane,3-isocyanatopropyltrimethoxysilane,tris(3-trimethoxysilylpropyl)isocyanurate,(3-triethoxysilylpropyl)-t-butylcarbamate,triethoxysilylpropylethylcarbamate, 3-thiocyanatopropyltriethoxysilane,and combinations thereof.

Clause 30. The system of Clause 26, wherein the tubular body comprises(a) platinum or platinum alloy filaments, combined with (b)cobalt-chromium alloy filaments.

Clause 31. The system of Clause 30, wherein the platinum or platinumalloy filaments possess a layer of the phosphorylcholine, and whereinthe cobalt-chromium alloy filaments possess a silane intermediate layerbetween the cobalt-chromium alloy filaments and the phosphorylcholine.

Clause 32. The system of Clause 30, wherein the phosphorylcholine ischemically bonded directly to the platinum or platinum alloy filaments.

Clause 33. The system of Clause 30, wherein the phosphorylcholine iscovalently bonded to the platinum or platinum alloy filaments.

Clause 34. The system of Clause 30, wherein the phosphorylcholine ischemically bonded to a silane over the cobalt-chromium alloy filaments.

Clause 35. The system of Clause 34, wherein the phosphorylcholine iscovalently bonded to a silane over the cobalt-chromium alloy filaments.

Clause 36. The system of Clause 26, wherein the tubular body comprisesplatinum or platinum alloy filaments.

Clause 37. The system of Clause 36, wherein the phosphorylcholine iscovalently bonded to the platinum or platinum alloy filaments.

Clause 38. The system of Clause 36, wherein the phosphorylcholine ischemically bonded to the platinum or platinum alloy filaments.

Clause 39. The system of Clause 26, wherein the tubular body has asidewall formed by the braided filaments, the sidewall having aplurality of pores therein, the plurality of pores being sized toinhibit flow of blood through the sidewall into an aneurysm to a degreesufficient to lead to thrombosis and healing of the aneurysm when thetubular body is positioned in a blood vessel and adjacent to theaneurysm.

Clause 40. The system of Clause 26, wherein the tubular body has asidewall formed by the braided filaments, the sidewall having aplurality of pores therein, the plurality of pores having an averagepore size that is less than or equal to 500 microns.

Clause 41. The system of Clause 26, wherein the tubular body is heat setso that the filaments are at their least-stressed configuration in thetubular body.

Clause 42. The system of Clause 26, wherein the outer surface is anoutermost surface of the filaments.

Clause 43. The system of Clause 26, wherein the tubular body comprises astent.

Clause 44. The system of Clause 26, wherein the phosphorylcholine has athickness from about 1 to about 100 nanometers.

Clause 45. The system of Clause 26, wherein the tubular body isself-expanding.

Clause 46. The system of Clause 26, wherein the tubular body is lessthrombogenic than an identical body whose braided filaments are entirelybare metal.

Clause 47. The system of Clause 26, wherein the tubular body exhibits anelapsed time before peak thrombin formation that is at least 1.5 timesthe elapsed time before peak thrombin formation for an identical tubularbody whose braided filaments are entirely bare metal.

Clause 48. The system of Clause 26, wherein the tubular body exhibits apeak thrombin concentration that is less than 0.8 times the peakthrombin concentration for an identical tubular body whose braidedfilaments are entirely bare metal.

Clause 49. The system of Clause 26, further comprising a microcatheterconfigured to slidably receive the core assembly and tubular member in alumen of the microcatheter.

Clause 50. A method of treating an aneurysm formed in a wall of a parentblood vessel, the method comprising:

-   -   deploying the tubular body of any preceding Clause into the        parent blood vessel so that a sidewall of the medical device        extends across a neck of the aneurysm, thereby causing        thrombosis within the aneurysm.

Clause 51. A method of treating an aneurysm formed in a wall of a parentblood vessel of a patient, the method comprising:

-   -   deploying a flow-diverting metallic stent having a        phosphorylcholine outer surface of less than 100 nanometers in        thickness in the parent blood vessel across the neck of the        aneurysm, so as to treat the aneurysm; and    -   either (a) prescribing to the patient a reduced protocol of        anti-platelet medication, in comparison to a protocol that would        be prescribed to the patient if an otherwise similar stent that        lacks the phosphorylcholine outer surface were deployed in the        patient, or (b) declining to prescribe to the patient any        anti-platelet medication.

Clause 52. The method of Clause 51, wherein the stent comprises thetubular body of any preceding Clause.

Clause 53. The method of Clause 51, wherein the patient is one who hasbeen diagnosed as being at risk of an intracranial hemorrhage.

Clause 54. The method of Clause 51, wherein the patient is one who hasbeen diagnosed as being at risk of a cerebral hemorrhage from ananeurysm.

Clause 55. The method of Clause 51, wherein the parent blood vessel isan intracranial artery.

Clause 56. The method of Clause 51, further comprising accessing atreatment region near the aneurysm by inserting a microcatheter into theparent vessel, and delivering the stent through the microcatheter to thetreatment region.

Clause 57. The method of Clause 51, wherein the stent exhibits anelapsed time before peak thrombin formation that is at least 1.5 timesthe elapsed time of a similar stent that lacks the phosphorylcholineouter surface.

Clause 58. The method of Clause 51, wherein the stent exhibits a peakthrombin concentration that is less than 0.8 times the peak thrombinconcentration for a similar stent that lacks the phosphorylcholine outersurface.

Clause 59. A method of treating an aneurysm formed in a wall of a parentblood vessel of a patient, the method comprising:

-   -   deploying a flow-diverting stent in the parent blood vessel        across the neck of the aneurysm, so as to treat the aneurysm, at        least a portion of the stent having a phosphorylcholine outer        surface of less than 100 nanometers in thickness so that the        stent exhibits a peak thrombin concentration that is less than        0.8 times the peak thrombin concentration of an otherwise        similar stent that lacks the phosphorylcholine outer surface;        and    -   either (a) prescribing to the patient a reduced protocol of        anti-platelet medication, in comparison to a protocol that would        be prescribed to the patient if the otherwise similar stent that        lacks the phosphorylcholine outer surface were deployed in the        patient, or (b) declining to prescribe to the patient any        anti-platelet medication.

Clause 60. The method of Clause 59, wherein the stent comprises thetubular body of any preceding Clause.

Clause 61. The method of Clause 59, wherein the patient is one who hasbeen diagnosed as being at risk of an intracranial hemorrhage.

Clause 62. The method of Clause 59, wherein the patient is one who hasbeen diagnosed as being at risk of a cerebral hemorrhage from ananeurysm.

Clause 63. The method of Clause 59, wherein the parent blood vessel isan intracranial artery.

Clause 64. The method of Clause 59, further comprising accessing atreatment region near the aneurysm by inserting a microcatheter into theparent vessel, and delivering the stent through the microcatheter to thetreatment region.

Additional features and advantages of the subject technology will be setforth in the description below, and in part will be apparent from thedescription, or may be learned by practice of the subject technology.The advantages of the subject technology will be realized and attainedby the structure particularly pointed out in the written description andembodiments hereof as well as the appended drawings.

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory and areintended to provide further explanation of the subject technology.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are included to provide furtherunderstanding of the subject technology and are incorporated in andconstitute a part of this specification, illustrate aspects of thedisclosure and together with the description serve to explain theprinciples of the subject technology.

FIG. 1 is a side view of a stent including an outer layer thereon,according to some embodiments.

FIG. 2A is an enlarged view of the stent shown in FIG. 1, according tosome embodiments.

FIGS. 2B-2C are detail views of a pore of the stent of FIG. 1, invarious conditions.

DETAILED DESCRIPTION

In the following detailed description, numerous specific details are setforth to provide a full understanding of the subject technology. Itshould be understood that the subject technology may be practicedwithout some of these specific details. In other instances, well-knownstructures and techniques have not been shown in detail so as not toobscure the subject technology. Further, although the present disclosuremay refer to embodiments in which the apparatus is a stent, aspects ofthe embodiments disclosed herein can be used with any implantabledevice, such as coils, filters, scaffolds, ventricular assist devices,self-expanding and balloon-expandable stents, and other devices.

The present disclosure provides devices having coatings, surfacetreatments and/or layers thereon, as well as embodiments for applyingcoatings/surface treatments/layers to medical devices. Substrates usedto form medical devices in accordance with the present disclosure may beformed of any suitable substance, including inert materials such asmetals, glass, ceramics, combinations thereof, and the like.

In embodiments, substrates of the present disclosure may be formed ofinert materials such as glass, ceramics, and/or metals. Suitable metalsinclude gold, silver, copper, steel, aluminum, titanium, cobalt,chromium, platinum, nickel, alloys thereof, combinations thereof, andthe like. Suitable alloys include nickel-titanium (e.g., nitinol),cobalt-nickel, cobalt-chromium, and platinum-tungsten. One suitablecobalt based alloy is 35N LT™ available from Fort Wayne Metals of FortWayne, Ind., USA.

In accordance with some embodiments disclosed herein, a medical device(e.g., stent) is provided that has reduced thrombogenicity. Further, insome embodiments, such a device can be braided and/or have a flowdiverting section.

The medical devices of the present disclosure can include one or morepolymer layers thereon. In embodiments, the present disclosure providesfor the use of silanes to form an optional intermediate layer whichbinds to the substrate. In embodiments, polymer layers, layers ofbioactive agents, combinations thereof, and the like, may then beapplied to and bound directly to the substrate and/or any intermediatesilane layer.

Silanes which may be utilized in forming the optional silane layer mayhave at least one functional group including, but not limited to,acrylate, methacrylate, aldehyde, amino, epoxy, ester, combinationsthereof, and the like. In embodiments, additional silanes which may beused in forming the silane layer include, but are not limited to,3-glycidyloxypropyl trimethoxysilane (GPTS),2-(3,4-epoxycyclohexyl)ethyl-triethoxysilane,2-(3,4-epoxycyclohexyl)ethyl-trimethoxysilane,(3-glycidoxypropyl)trimethoxysilane, (3-glycidoxypropyl)triethoxysilane,5,6-epoxyhexyltriethoxysilane, (3-glycidoxypropyl)methyldiethoxysilane,(3-glycidoxypropyl)methyldimethoxysilane,(3-glycidoxypropyl)dimethylethoxysilane,3-isocyanatopropyltriethoxysilane,(isocyanatomethyl)methyldimethoxysilane,3-isocyanatopropyltrimethoxysilane,tris(3-trimethoxysilylpropyl)isocyanurate,(3-triethoxysilylpropyl)-t-butylcarbamate,triethoxysilylpropylethylcarbamate, 3-thiocyanatopropyltriethoxysilane,combinations thereof, and the like.

In embodiments, the silanes used to form the silane layer may be insolution, which is then applied to the substrate. Suitable solvents forforming the solution include, for example, ethanol, toluene, water,deionized water, methanol, isopropyl alcohol, n-butanol,dimethylformamide (DMF), dimethyl sulfoxide (DMSO), ethyl acetate,propylene glycol monomethyl ether acetate (PM acetate), toluene,chloroform, dichloromethane, combinations thereof, and the like. Thesolvents may be present in amounts from about 0.1% to about 99.9% byweight of the solution, in embodiments from about 50% to about 99.8% byweight of the solution. In some embodiments, the solution may includeethanol and water at a ratio from about 95%/5%. The silane may be insolution at a concentration from about 0.1% to about 99.9%, inembodiments from about 0.2% to about 50%.

In embodiments, a suitable solution for applying a silane layer mayinclude GPTS in 95%/5% ethanol/water.

To apply the polymer layer and/or optional silane layer to thesubstrate, it may be desirable to first clean the substrate surface. Forexample, the substrate surface may first be subjected to sonication andcleaned with a suitable solvent such as acetone, isopropyl alcohol,ethanol, methanol, combinations thereof, and the like. Sonication mayoccur for a period of time from about 1 minute to about 20 minutes, inembodiments from about 5 minutes to about 15 minutes. However, inembodiments, sonication may occur for longer periods, up to 1 hour, upto 2 hours, or more than 2 hours. The solvents used in thesonication/cleaning may be applied as mixtures, or individual solventsmay be applied sequentially, one or more times. The sonication may occurat room temperature, e.g. at about 21° C., or at temperatures from about18° C. to about 55° C., in embodiments from about 40° C. to about 50°C., in embodiments about 45° C.

After cleaning, the substrates may be subjected to a treatment toenhance the formation of hydroxyl groups (sometimes referred to, herein,as hydroxylation). The surface of the substrate may be hydroxylated bysubjecting the surface to a treatment with sodium hydroxide, nitricacid, sulfuric acid, hydrochloric acid, ammonium hydroxide, hydrogenperoxide, tert-butyl hydroperoxide, potassium dichromate, perchloricacid, oxygen plasma, water plasma, corona discharge, ozone, UV,combinations thereof, and the like. The material used for hydroxylationmay be at a concentration from about 10% to about 100%, in embodimentsfrom about 15% to about 25%, in embodiments about 20%. Hydroxylation mayoccur over a period of time from about 0.5 hours to about 2.5 hours, ormore than 2.5 hours, in embodiments from about 1 hour to about 2 hours,in embodiments about 1.5 hours, at room temperature. Hydroxylation mayalso occur with shaking from about 100 to about 160 revolutions perminute (rpm), in embodiments from about 120 to about 140 rpm, inembodiments about 130 rpm.

After hydroxylation, the substrate may be rinsed with a suitablematerial, such as deionized water, ethanol, methanol, combinationsthereof, and the like.

The hydroxylated substrate may then be treated with the polymer and/orsilanes described above. For example, in embodiments, the substrate maybe immersed in a solution including the silane for a period of time fromabout 0.5 hours to about 3.5 hours, in embodiments from about 1 hour toabout 3 hours, in embodiments for about 2 hours, at room temperature.

The silane solution possessing the substrate may also be subjected toshaking at a rate from about 100 to about 160 revolutions per minute(rpm), in embodiments from about 120 to about 140 rpm, in embodimentsabout 130 rpm.

After immersion in the silane materials, the substrate may then bedipped in, or sprayed with, a suitable material, such as ethanol,toluene, deionized water, methanol, isopropyl alcohol, n-butanol,dimethylformamide (DMF), dimethyl sulfoxide (DMSO), ethyl acetate, PMacetate, toluene, chloroform, dichloromethane, combinations thereof, andthe like, from one time to about 5 times, in embodiments about 3 times.The substrate with the silanes thereon may then be heated at atemperature from about 30° C. to about 150° C., in embodiments fromabout 70° C. to about 90° C., in embodiments about 80° C. Heating mayoccur for a time from about 5 minutes to about 25 minutes, or more than25 minutes, in embodiments from about 10 minutes to about 20 minutes, inembodiments about 15 minutes.

Where applied to a substrate, the silane layer may have a thickness lessthan 50 nanometers, or less than 20 nanometers, or less than 10nanometers, in embodiments from about 1 nanometer to about 10nanometers.

Once the optional silane layer has been formed, the medical device maybe treated with additional components to form an outer layer on thesilane layer. For example, bioactive agents may bind to free functionalgroups of the silane layer. Similarly, polymeric and/or monomericmaterials may bind free functional groups on the substrate and/oroptional silane layer, with or without bioactive agents.

Suitable polymeric and/or monomeric materials which may be utilized toform an outer layer on the medical device of the present disclosure,binding to either the substrate, the optional silane layer describedabove, or both, include any material suitable for use in the medicaldevice. Such materials may provide desirable properties to the medicaldevice, including reduced thrombogenicity, lubricity, drug delivery,protein or DNA delivery, prevention of restenosis, cell and proteinadhesion, lubricity, RNA and/or gene delivery, anti-microbial,non-fouling, promoting endothelialization, combinations thereof, and thelike.

In embodiments, suitable polymeric and/or monomeric materials which maybind to the substrate and/or optional silane layer, and be used to forman outer layer on the medical device of the present disclosure, includephosphorylcholines. Suitable phosphorylcholines include2-methacryloyloxyethyl phosphorylcholine (MPC), 2-acryloyloxyethylphosphorylcholine, and the like, and combinations thereof. Otherphosphorylcholines may be utilized, including phosphorylcholines basedupon monomers including, but not limited to,2-(meth)acryloyloxyethyl-2′-(trimethylammonio)ethyl phosphate,3-(meth)acryloyloxypropyl-2′-(trimethylammonio)ethyl phosphate,4-(meth)acryloyloxybutyl-2′-(trimethylammonio)ethyl phosphate,5-(meth)acryloyloxypentyl-2′-(trimethylammonio)ethyl phosphate,6-(meth)acryloyloxyhexyl-2′-(trimethylammonio)ethyl phosphate,2-(meth)acryloyloxyethyl-2′-(triethylammonio)ethyl phosphate,2-(meth)acryloyloxyethyl-2′-(tripropylammonio)ethyl phosphate,2-(meth)acryloyloxyethyl-2′-(tributylammonio)ethyl phosphate,2-(meth)acryloyloxypropyl-2′-(trimethylammonio)ethyl phosphate,2-(meth)acryloyloxybutyl-2′-(trimethylammonio)ethyl phosphate,2-(meth)acryloyloxypentyl-2′-(trimethylammonio)ethyl phosphate,2-(meth)acryloyloxyhexyl-2′-(trimethylammonio)ethyl phosphate,2-(meth)acryloyloxyethyl-3′-(trimethylammonio)propyl phosphate,3-(meth)acryloyloxypropyl-3′-(trimethylammonio)propyl phosphate,4-(meth)acryloyloxybutyl-3′-(trimethylammonio)propyl phosphate,5-(meth)acryloyloxypentyl-3′-(trimethylammonio)propyl phosphate,6-(meth)acryloyloxyhexyl-3′-(trimethylammonio)propyl phosphate,2-(meth)acryloyloxyethyl-4′-(trimethylammonio)butyl phosphate,3-(meth)acryloyloxypropyl-4′-(trimethylammonio)butyl phosphate,4-(meth)acryloyloxybutyl-4′-(trimethylammonio)butyl phosphate,5-(meth)acryloyloxypentyl-4′-(trimethylammonio)butyl phosphate,6-(meth)acryloyloxyhexyl-4′-(trimethylammonio)butylphosphate, andcombinations thereof. As used herein, “(meth)acryl” includes bothmethacryl and/or acryl groups. Such phosphorylcholines include thosecommercially available as LIPIDURE® MPCs (including for exampleLIPIDURE®-NH01, a reactive MPC) from NOF Corporation of Tokyo, Japan.Phosphorylcholines can include reactive phosphorylcholines, for examplein the form of a copolymer of phosphorylcholine and a reactive chemicalgroup. The reactive group can be, for example, amine, hydroxyl, epoxy,silane, aldehyde, carboxylate or thiol.

In embodiments, the phosphorylcholines used to form the polymer layermay be in solution, which is then applied to the substrate and/oroptional silane layer. Suitable solvents for forming the solutionpossessing the polymer, such as the above phosphorylcholines, include,for example, ethanol, water, deionized water, methanol, isopropylalcohol, n-butanol, dimethylformamide (DMF), dimethyl sulfoxide (DMSO),ethyl acetate, PM acetate, toluene, chloroform, dichloromethane,combinations thereof, and the like. The polymer may be present inamounts from about 0.5% to about 95% by weight of the solution, inembodiments from about 1% to about 50% by weight of the solution. Insome embodiments, the solution may include MPC at a concentration ofabout 5%.

The polymer may be applied to the substrate and/or optional silane layerusing various methods, including dipping, spraying, brushing,combinations thereof, and the like. For example, in embodiments, asubstrate, optionally possessing a silane layer, may be immersed in asolution including the polymer for a period of time from about 30seconds to about 90 seconds, in embodiments from about 45 seconds toabout 75 seconds, in embodiments for about 45 seconds, at roomtemperature. Additional information on polymer application methods maybe found in U.S. patent application Ser. No. 13/844,577, filed Mar. 15,2013, titled COATED MEDICAL DEVICES AND METHODS OF MAKING AND USINGSAME, the entirety of which is hereby incorporated by reference hereinand made a part of this specification.

After immersion in the polymer solution, the substrate, now possessing apolymer layer either directly bound to the substrate, the optionalsilane layer, or both, may be heated at a temperature from about 60° C.to about 100° C., in embodiments from about 70° C. to about 90° C., inembodiments about 80° C. Heating may occur for a time from about 15minutes to about 45 minutes, or more than 45 minutes, in embodimentsfrom about 20 minutes to about 35 minutes, in embodiments about 30minutes.

After heating, the device may again be washed. For example, the devicemay be subjected to sonication and cleaned with water, ethanol,methanol, isopropyl alcohol, n-butanol, dimethylformamide (DMF),dimethyl sulfoxide (DMSO), ethyl acetate, PM acetate, toluene,chloroform, dichloromethane, toluene, combinations thereof, and thelike. Sonication may occur for a period of time from about 1 minute toabout 10 minutes, or more than 10 minutes, in embodiments from about 2minutes to about 8 minutes, in embodiments about 5 minutes. Sonicationmay occur at room temperature.

After this cleaning, the device may be rinsed with a suitable material,such as water, methanol, isopropyl alcohol, n-butanol, dimethylformamide(DMF), dimethyl sulfoxide (DMSO), ethyl acetate, PM acetate, toluene,chloroform, dichloromethane, combinations thereof, and the like. Thedevice may then be heated at a temperature from about 60° C. to about100° C., in embodiments from about 70° C. to about 90° C., inembodiments about 80° C. Heating may occur for a time from about 5minutes to about 25 minutes, or more than 25 minutes, in embodimentsfrom about 10 minutes to about 20 minutes, in embodiments about 15minutes.

Upon completion of this heating step, the device is now ready forpackaging in any material suitable for use in packaging medical devices.

The polymer layer on the resulting medical device may have a thicknessless than about 2000 nanometers, in embodiments less than about 1000nanometers, in embodiments less than about 500 nanometers, inembodiments less than about 250 nanometers, in embodiments less thanabout 100 nanometers, in embodiments less than about 50 nanometers, inembodiments less than about 25 nanometers, in embodiments less thanabout 10 nanometers, in embodiments from about 1 nanometer to about 100nanometers, in embodiments from about 1 nanometer to about 50nanometers, in embodiments from about 1 nanometer to about 25nanometers, in embodiments from about 1 nanometer to about 10nanometers. In embodiments, the polymer layer is the outermost layer of,and/or forms the outer surface of, the medical device and/or anycomponents forming the device, e.g., filaments forming a stent.

As noted above, bioactive agents may be added to a medical device of thepresent disclosure, either as part of the device, and/or as part of thelayer(s) applied in accordance with the present disclosure. A “bioactiveagent,” as used herein, includes any substance or mixture of substancesthat provides a therapeutic or prophylactic effect; a compound thataffects or participates in tissue growth, cell growth and/or celldifferentiation; a compound that may be able to invoke or prevent abiological action such as an immune response; or a compound that couldplay any other role in one or more biological processes. A variety ofbioactive agents may be incorporated into the medical device. Moreover,any agent which may enhance tissue repair, limit the risk of restenosis,and modulate the mechanical or physical properties of the medicaldevice, such as a stent, may be added during the preparation of themedical device. In embodiments, the bioactive agent may be added to thepolymer used to form the outer layer of the medical device.

Examples of classes of bioactive agents which may be utilized inaccordance with the present disclosure include antimicrobials,analgesics, anesthetics, antihistamines, anti-inflammatories,cardiovascular drugs, diagnostic agents, sympathomimetics,cholinomimetics, antimuscarinics, antispasmodics, hormones, growthfactors, muscle relaxants, adrenergic neuron blockers, antineoplastics,immunogenic agents, immunosuppressants, steroids, lipids,lipopolysaccharides, polysaccharides, and enzymes. It is also intendedthat combinations of bioactive agents may be used.

Other bioactive agents which may be in the present disclosure includeantirestenotic agents, including paclitaxel, paclitaxel derivatives,rapamycin, everolimus, sirolimus, taxane QP-2, actinomycin D,vincristine, methotrexate, angiopeptin, mitomycin, BCP 678, C-mycantisense, sirolimus derivatives, tacrolimus, everolimus, ABT-578,biolimus A9, tranilast, dexamethasone, methylprednisolone, interferon,leflunomide, cyclosporin, halofuginone, C-proteinase inhibitors,metalloproteinase inhibitors, batimastat, propyl hydroxylase inhibitors,VEGF, 17-β-estradiol, BCP 671, HMG CoA reductase inhibitors,combinations thereof, and the like.

Yet other bioactive agents include sympathomimetic agents; vitamins;anticholinergic agents (e.g., oxybutynin); cardiovascular agents such ascoronary vasodilators and nitroglycerin; alkaloids; analgesics;non-narcotics such as salicylates, aspirin, acetaminophen,d-propoxyphene and the like; anti-cancer agents; anti-inflammatoryagents such as hormonal agents, hydrocortisone, prednisolone,prednisone, non-hormonal agents, allopurinol, indomethacin,phenylbutazone and the like; prostaglandins and cytotoxic drugs;antibacterials; antibiotics; anti-fungals; anti-virals; anticoagulants;and immunological agents.

Other examples of suitable bioactive agents which may be included in thepresent disclosure include: viruses and cells; peptides, polypeptidesand proteins, as well as analogs, muteins, and active fragments thereof;immunoglobulins; antibodies; cytokines (e.g., lymphokines, monokines,chemokines); blood clotting factors; hemopoietic factors; interleukins(IL-2, IL-3, IL-4, IL-6); interferons (β-IFN, (α-IFN and γ-IFN));erythropoietin; nucleases; tumor necrosis factor; colony stimulatingfactors (e.g., GCSF, GM-CSF, MCSF); insulin; anti-tumor agents and tumorsuppressors; blood proteins; gonadotropins (e.g., FSH, LH, CG, etc.);hormones and hormone analogs (e.g., growth hormone); vaccines (e.g.,tumoral, bacterial and viral antigens); somatostatin; antigens; bloodcoagulation factors; growth factors (e.g., nerve growth factor,insulin-like growth factor); protein inhibitors; protein antagonists;protein agonists; nucleic acids such as antisense molecules, DNA, andRNA; oligonucleotides; and ribozymes.

Suitable medical devices which may be prepared in accordance with thepresent disclosure include, but are not limited to, stents, filters,stent coatings, grafts, catheters, stent/grafts, clips and otherfasteners, staples, sutures, pins, screws, prosthetic devices, drugdelivery devices, anastomosis rings, surgical blades, contact lenses,intraocular lenses, surgical meshes, knotless wound closures, sealants,adhesives, intraocular lenses, anti-adhesion devices, anchors, tunnels,bone fillers, synthetic tendons, synthetic ligaments, tissue scaffolds,stapling devices, buttresses, lapbands, orthopedic hardware, pacers,pacemakers, and other implants and implantable devices.

In embodiments, most of the accessible surfaces of the substrate may becovered with the polymer layer and optional silane layer. In yet otherembodiments, the entire substrate is covered. The layers may cover fromabout 1% to about 100% of the area of the substrate, in embodiments astent, in embodiments from about 20% to about 90% of the area of thesubstrate.

As noted above, in embodiments, the medical device in accordance withthe present disclosure is a stent. Any stent may be treated inaccordance with the methods herein. The stent may be a braided stent orother form of stent such as a laser-cut stent, roll-up stent, balloonexpandable stent, self-expanding stent, knitted stent, and the like.

In embodiments, a braided vascular device such as a stent is braidedfrom filaments which are formed from metal alloys and/or otherhigh-temperature materials. The resulting braid is then heat-treated or“heat-set” at high temperature in order to reduce internal stresses inthe filaments and/or increase or impart a self-expanding capability ofthe stent. Filaments making up the tubular body of a stent that has beenheat set are in their least-stressed or a reduced-stressed state whenthe stent is in the configuration it was in during heat setting. Such aleast-stressed or reduced-stressed state can include an expanded orfully expanded state.

The stent can optionally be configured to act as a “flow diverter”device for treatment of aneurysms, such as those found in blood vesselsincluding arteries in the brain or within the cranium, or in otherlocations in the body such as peripheral arteries. The stent can, inembodiments, include those sold as PIPELINE™ Embolization Devices byCovidien, Mansfield, Mass.. Such devices also include those disclosed inU.S. Pat. No. 8,267,986, issued Sep. 18, 2012, titled VASCULAR STENTINGFOR ANEURYSMS, the entire disclosure of which is incorporated byreference herein.

For example, in accordance with the present disclosure, a device havinga flow diverting section can have pores with a “flow diverting poresize.” A “flow diverting pore size” can refer to pores having an averagepore size (in at least a section of a device) that is sufficiently smallto interfere with or inhibit fluid exchange through the pores of thatsection. For example, a device (e.g., stent) can have an active sectionor a flow diverting section with a flow diverting pore size when thepores of the section are sized to inhibit flow of blood through thesidewall into an aneurysm to a degree sufficient to lead to thrombosisand healing of the aneurysm when the device/stent is positioned in ablood vessel and adjacent to or across the neck of the aneurysm.

For example, a flow diverting pore size can be achieved when pores inthe flow diverting or active section (or in the stent as a whole) havean average pore size of less than about 500 microns when the device(e.g., stent) is in the expanded state. (When “expanded state” is usedherein to specify braided stent parameters such as pore sizes, theexpanded state is one that the stent will self-expand to without anyexternal expansive forces applied, and without any external longitudinalstretching or compressive forces applied. For simplicity of measurement,this expanded state can be one that the stent will self-expand to withina straight glass cylindrical tube with an inside diameter that issmaller than the maximum diameter to which the stent will self-expand inthe absence of any containment or external forces.) In some embodiments,the average pore size can be less than about 320 microns. Someembodiments disclosed herein enable and provide a device and methods ofmanufacturing in which the device has a flow diverting section or flowdiverting sidewall that has reduced thrombogenicity, or in which thedevice as a whole possesses flow diverting properties and reducedthrombogenicity.

Accordingly, some embodiments provide a device, such as a braided stent,that can have a flow diverting section or other portion of the devicethat provides embolic properties so as to interfere with blood flow in(or into) the body space (e.g., an aneurysm) in (or across) which thedevice is deployed. The porosity and/or pore size of one or moresections of the device can be selected to interfere with blood flow to adegree sufficient to thrombose the aneurysm or other body space.

For example, some embodiments provide a device (e.g., stent) that can beconfigured to interfere with blood flow to generally reduce the exchangeof blood between the parent vessel and an aneurysm, which can inducethrombosis of the aneurysm. A device (or a device component, such as asidewall of a stent or a section of such a sidewall) that thusinterferes with blood flow can be said to have a “flow diverting”property.

Additionally, in some embodiments, a device (e.g., stent) can beprovided with a porosity in the range of 5%-95% may be employed in theexpanded braid. In some embodiments, a porosity in the range of 30%-90%may be employed. Further, a porosity in the range of 50%-85% may beemployed. The porosity can be computed as the percentage of the totalouter surface area of the stent that is open, wherein the total outersurface area is the sum of the open (pore-occupied) surface area and thesolid (filament-occupied) surface area.

Further, in some embodiments, a device (e.g., stent) can be providedwith a pore size from about 20 to about 300 microns (inscribeddiameter). In some embodiments, a pore size from about 25 to about 250microns (inscribed diameter) may be employed. In some embodiments, apore size from about 50 to about 200 microns (inscribed diameter) may beemployed.

Methods of treatment and methods of manufacturing embodiments of thedevices (e.g., stents) disclosed herein are also provided.

Some embodiments of processes disclosed herein include mounting ormaintaining a braided device (e.g., stent) in a longitudinally stretchedconfiguration during the process of applying the polymer layer and anyoptional silane layer. Such a device can have an expanded configurationin which the pores thereof are generally circumferentially elongated,which results in a decreased pore size or a relatively “closed”configuration. In contrast, the pore size is increased or in arelatively “open” configuration when the device is in the longitudinallystretched configuration. In the longitudinally stretched configuration,many, if not all, of the pores of the device can be opened to anenlarged pore size, or to a generally maximum pore size.

For example, in some embodiments, the longitudinally stretchedconfiguration can open the pores by orienting the individual filamentsof the device to create a pattern of open-pore quadrilaterals, such assquares, rectangles, parallelograms, rhombuses, trapezoids, etc., whichcan allow the pore size to be generally maximized. Further, thequadrilaterals can be formed by filaments that cross at angles fromabout 0° to about 15° from a right angle. In some embodiments, theangles can be from about 0° to about 10° from a right angle. In someembodiments, the angles can be from about 0° to about 5° from a rightangle. Additionally, in some embodiments, the filaments can formright-angled quadrilaterals, such as squares and rectangles, whichallows the pore size to be maximized. However, not every pore shapecircumscribed by the filaments may be a right-angled quadrilateral, andsome variation between pores in the same or different sections of adevice is possible.

In embodiments, the device (e.g., stent) can take the form of a vascularoccluding device, a revascularization device, and/or an embolizationdevice. In some embodiments, the device can be an expandable stent madeof two or more filaments. The filaments can be formed of known flexiblematerials including platinum, cobalt, chromium, nickel, alloys thereof,and combinations thereof. In some embodiments, the filaments can be wirehaving a generally circular, round or ovoid cross-section. Further, thefilaments can be configured such that the device is self-expanding. Insome embodiments, the device can be fabricated from a first group offilaments made of platinum alloyed with tungsten (e.g., about 8%tungsten), and a second group of filaments made of cobalt-chromium alloyor cobalt-nickel alloy (e.g., 35N LT™). In other embodiments, one ormore of the filaments can be formed of a biocompatible metal material ora biocompatible polymer.

The wires or filaments can be braided into a resulting tubular,lattice-like structure. In at least one embodiment, during braiding orwinding of the device (e.g., stent), the filaments can be braided usinga 1-over-2-under-2 pattern. In other embodiments, however, other methodsof braiding can be followed, without departing from the scope of thedisclosure. The device can exhibit a porosity configured to reducehemodynamic flow into and/or induce thrombosis within, for example, ananeurysm, but simultaneously allow perfusion to an adjacent branchvessel whose ostium is crossed by a portion of the device. As will beappreciated, the porosity of the device can be adjusted by “packing” thedevice during deployment, as known in the art. The ends of the devicecan be cut to length and therefore remain free for radial expansion andcontraction. The device can exhibit a high degree of flexibility due tothe materials used, the density of the filaments, and the fact that theends of the wires or filaments are not secured to each other.

In addition to the methods described above, in embodiments, combinationsof filaments of the present disclosure may have different polymer layerapplied thereto. For example, in embodiments, a medical device of thepresent disclosure may include platinum or platinum alloy filamentsbraided with or combined with cobalt-nickel or cobalt-chromium alloyfilaments. The platinum or platinum alloy filaments may possess a layerof phosphorylcholine (e.g. with no intervening layers between thefilament and the phosphorylcholine), while the cobalt-nickel orcobalt-chromium alloy filaments may possess a silane intermediate layerbetween the alloy filaments and an outer layer of phosphorylcholine. Insuch cases, the phosphorylcholine may directly bind to the platinum orplatinum alloy filaments by covalent bonding, chemical bonding,combinations thereof, and the like. Similarly, the phosphorylcholine maybe chemically bonded to a silane layer over the cobalt-nickel orcobalt-chromium alloy filaments, or the phosphorylcholine may becovalently bonded to a silane layer over the cobalt-nickel orcobalt-chromium alloy filaments.

Other combinations are also contemplated. For example, a platinum orplatinum alloy filament may also possess an intermediate silane layer inaddition to an outer phosphorylcholine layer, while a cobalt-nickel orcobalt-chromium alloy filament may possess an outer phosphorylcholinelayer but no intermediate silane layer.

FIG. 1 illustrates a tubular, self-expanding device, shown as a stent100, including a polymer layer 110 disposed along at least a portionthereof. An optional silane layer (not shown) may be between thefilaments used to form the stent 100 and polymer layer 110. The tubularstent 100 includes an elongate hollow body which can be formed from aplurality of braided filaments as discussed herein. Some embodimentsdisclosed herein can include a polymer layer along the entire length ofthe stent or merely along only a portion thereof. The stent 100 caninclude a flow diverting portion 112. The flow diverting portion 112 caninclude a plurality of pores that have a flow diverting pore size;instead of or in addition to this property, the flow diverting portion112 can have a flow diverting porosity. The flow diverting portion 112can include a portion of the stent 100, or the entire stent. The flowdiverting pore size can be an average pore size within a relevantportion of the stent, e.g. within the flow diverting portion 112 or aportion thereof, or a “computed” pore size, one that is computed frommeasured or nominal basic stent parameters such as braid angle, numberof filaments, filament size, filament diameter, stent diameter,longitudinal picks per inch, radial picks per inch, etc. Such a computedpore size can be considered to be one type of average pore size. Theflow diverting pore size can have a size that interferes with orinhibits blood flow through the sidewall of the stent 100, for example,between the parent vessel and an aneurysm sufficient to induce or leadto thrombosis of the aneurysm. The layer can be disposed partially orentirely along the flow diverting portion 112, or along another portionof the stent 100.

In some embodiments, the pores of the flow diverting portion 112 canhave an average pore size of less than 500 microns (inscribed diameter),or from about 20 to about 300 microns (inscribed diameter). Further, theaverage pore size can be from about 25 to about 250 microns (inscribeddiameter). Furthermore, the average pore size can be from about 50 toabout 200 microns (inscribed diameter).

The average pore size of the pores in the flow diverting portion 112 canbe the average size of the pores measured with or without layermaterials disposed thereon. Thus, the average pore size of the flowdiverting portion of a bare stent can be within the flow divertingranges. Further, the average pore size of the flow diverting portion ofa stent can be within the flow diverting ranges. Furthermore, the flowdiverting portion 112 can possess pores having sizes above or below therange of the average pore size.

FIG. 2A illustrates an enlarged view of a section of the flow divertingportion 112 of the stent 100. In this embodiment, the flow divertingportion 112 includes a plurality of filaments 120 that are braidedtogether to form the tubular body of the stent 100. FIG. 2A illustratesthe self-expanding stent 100 in an expanded or relaxed state. In thisexpanded or relaxed state, the filaments 120 cross each other to formthe pores of the stent 100.

FIG. 2B illustrates a single pore 140 of the flow diverting section 112when in the relaxed state. The pore 140 is formed by a plurality offilaments 142, 144, 146, and 148. As shown, the filaments 142, 144 crosseach other to form an obtuse angle 150. In some embodiments, the obtuseangle 150 can be from about 110° to about 170°. Further, the obtuseangle 150 can be from about 120° to about 165°. Further, the obtuseangle 150 can be from about 130° to about 160°, and in some embodiments,the obtuse angle 150 can be about 150°.

Accordingly, the size or configuration of the pore 140 is “closed” orrelatively small in the expanded or relaxed state shown in FIG. 2B whencompared with the relatively “open” size of the pore 140 when the stent100 is in a longitudinally stretched configuration, as shown in FIG. 2C.FIG. 2C illustrates that the filaments 142, 144, 146, and 148 each crosseach other at angles 160 that approximate a right angle, e.g. withinfrom about 0° to about 15° from a right angle. In some embodiments, theangles 160 can be from about 0° to about 10° from a right angle. In someembodiments, the angles 160 can be from about 0° to about 5° from aright angle.

As noted above, filaments 142, 144, 146 and 148 may be made of differentmaterials having different layers thereon. For example, at least one offilaments 142, 144, 146 and 148 may be formed of a cobalt-nickel orcobalt-chromium alloy having both a silane layer and outer polymer layerapplied thereto (not shown), while at least one of the other filamentsmay be formed of a platinum or platinum alloy filament having a polymerlayer but no intermediate silane layer (not shown).

Additionally, in order to maximize the pore size, in some embodiments,the filaments can form right-angled quadrilaterals, such as squaresand/or rectangles. However, not every pore shape circumscribed by thefilaments may be a right-angled quadrilateral, and some variationbetween pores in the same or different sections of a stent is possible.

A device can be prepared according to some embodiments by braiding aplurality of filaments to form a braided stent, filter, or other braideddevice. The device can then be cleaned and heat treated, if necessary,to impart desired characteristics to the device. Thereafter, the devicecan have layers applied thereto using aspects of the methods disclosedherein.

Some embodiments of the devices and methods disclosed herein cantherefore provide a device, such as a stent or a braided stent, havingan outer layer that has low or no thrombogenicity, that also has a flowdiverting pore size and/or a flow diverting porosity that is/areexhibited throughout the entire stent, or in a flow diverting portion orsection of the stent.

The antithrombogenic polymer layer of the present disclosure reduces thethrombogenicity of the stent, device, section, etc., having the polymerlayer as compared to a similar stent, device, section, etc., lacking thepolymer layer. The reduction in thrombogenicity can be significant.Stents possessing layers according to the present disclosure have beentested for increased antithrombogenicity via thrombogram, in whichthrombin formation is measured by detecting the fluorescence of afluorescent additive in a test solution containing a sample of thestent. The time elapsed before peak thrombin formation was observed.Stents having polymer layers in accordance with the present disclosurewere found to result in a significant delay in peak thrombin formation,as compared to a similar stent which did not possess the polymer layer.In particular, the elapsed time before peak thrombin formation was foundto be about 4 times that of the similar stent lacking the polymer layer.Accordingly, the time before peak thrombin formation with the device,stent, section, etc. having the polymer layer can be more than 1.5times, or more than 2 times, or more than 3 times, or about 4 times thatof a similar device, stent, section, etc., lacking the polymer layer.

Stents having polymer layers in accordance with the present disclosurewere found to result in a significantly longer lag phase (the elapsedtime before the onset of thrombin formation), as compared to a similarstent which did not possess the polymer layer. In particular, the lagphase was found to be about 4 times that of the similar stent lackingthe polymer layer. Accordingly, the lag phase with the device, stent,section, etc. having the polymer layer can be more than 1.5 times, ormore than 2 times, or more than 3 times, or about 4 times that of asimilar device, stent, section, etc., lacking the polymer layer.

Stents having polymer layers in accordance with the present disclosurewere found to result in a significantly lower peak thrombinconcentration, as compared to a similar stent which did not possess thepolymer layer. In particular, the peak thrombin concentration was foundto be about 0.3 times that of the similar stent lacking the polymerlayer. Accordingly, the peak thrombin concentration with the device,stent, section, etc. having the polymer layer can be less than 0.8times, or less than 0.6 times, or less than 0.5 times, or about 0.3times that of a similar device, stent, section, etc., lacking thepolymer layer.

The thickness of the layers can be less than 100 nanometers, less than50 nanometers, less than 25 nanometers, or less than 10 nanometers, orfrom 1 nanometer to 10, 25, 50, or 100 nanometers. In embodiments, thethickness of the polymer layers is from about 2 to about 3 nanometers.In various embodiments of the stent, device, etc., the foregoingproperties can be present singly or in any combination, or not presentat all.

The processes and devices of the present disclosure have severaladvantages. The methods of the present disclosure, in some cases forminga silane on a medical device followed by forming a polymer layerthereon, may enhance adherence of the polymer layer to the substratesurface, thereby increasing coverage on the substrate. Medical deviceshaving polymer layers in accordance with the present disclosure thushave both a greater area of coverage, as well as an ability to retainthe outer layers and avoid delamination thereof. Moreover, use ofmaterials like phosphorylcholines as the polymer layer provides medicaldevices with very low thrombogenicity.

The following Examples are being submitted to illustrate embodiments ofthe present disclosure. These Examples are intended to be illustrativeonly and are not intended to limit the scope of the present disclosure.Also, parts and percentages are by weight unless otherwise indicated. Asused herein, “room temperature” refers to a temperature of from about20° C. to about 30° C.

EXAMPLE 1

Braided tubular stents were treated as follows. Each of the stents wasconfigured as follows: 48 braided filaments, of which 12 were ofplatinum alloyed with 8% tungsten, with 0.0012 inch filament diameter,12 were of cobalt-chromium (35N LT™), with 0.0012 inch filamentdiameter, and 24 were of 35NLT, with 0.0014 inch filament diameter;overall outside diameter 5.2 mm and longitudinal picks per inch of 275,both dimensions prevailing when in an expanded, unconstrained andunstretched condition.

The stents were provided in their cleaned, “bare metal” condition, andprepared as follows. Each stent was hydroxylated (−OH) via acid (e.g.HNO₃, or a mixture of H₂SO₄/H₂O₂), hydroxide (e.g., NaOH, or a mixtureof NH₃OH/H₂O₂) or plasma treatment (e.g., H₂O, O₃). The hydroxylatedmetal was rinsed with ethanol and deionized (DI) water, and placed intoa container with a 3-Glycidoxypropyltrimethoxysilane (GPTS) solution forsilanization. The GPTS was in a solution using 95%/5% by volume ofethanol/water mixture as a solvent at a concentration of GPTS of 2% byweight. The stent in solution was stirred at 130 revolutions per minute(rpm) for a period of time of about 90 minutes. The immersion andstirring process was performed under room temperature. After that, themetal was rinsed with ethanol and water, and cured at 80° C. for 15minutes. (The temperature can be changed to 110° C. or 120° C. and thecuring time can be varied from 15 minutes to 90 minutes.)

The silanized stent was then dipped into a reactive MPC solutioncontaining amino groups (LIPIDURE®-NH01, having a concentration of 5%)for 1 minute and cured at 80° C. for at least 30 minutes. After curing,the metal surface was washed with water in sonication for 5 minutes toeliminate non-covalently bonded polymer. The washed metal surface wasdried at a temperature of about 80° C. for 15 minutes. After completionof the process and trimming to length, the stents could be described astubular braided stents, open at each end with a lumen extending from oneend to the other, and with a an outer layer of MPC over the entirety ofthe stent filaments. The MPC was directly bonded to the platinum alloyfilaments, and bonded to a silane layer over the cobalt-chromium alloyfilaments.

Stents having layers applied thereto according to this Example 1 weretested for decreased thrombogenicity via thrombogram, employing thefollowing assay. A test solution was prepared as a mixture of (a)lyophilized platelets (catalog no. 101258, Biodata Corporation, Horsham,PA; reconstituted with TRIS buffered saline to a pre-mixture plateletconcentration of 200,000 per microliter), (b) lyophilized normal controlplasma (PlasmaCon N, catalog no. 30-201, R2 Diagnostics, South Bend, IN;reconstituted with water), (c) fluorogenic substrate(Z-Gly-Gly-Arg-AMC-HCl, catalog no. I-1140, Bachem Americas Inc.,Torrance, Calif.; pre-mixture concentration of 40 mM in dimethylsulfoxide), and (d) calcium chloride (catalog no. 223506-2.5 KG, SigmaAldrich, St. Louis, Mo.; pre-mixture concentration of 1M in water).These were combined in the test solution in proportions (by volume) of 1part fluorogenic substrate to 2 parts calcium chloride to 6 partsplatelets to 100 parts plasma. The final concentration of fluorogenicsubstrate was about 400 μM and the final concentration of calciumchloride was about 20 mM.

A calibration mixture was prepared by adding reference thrombincalibrator solution (catalog no. TS20.00, Stago Diagnostics Inc.,Parsippany, N.J.) and the fluorogenic substrate to the control plasma,in proportions (by volume) of 1 part substrate to 11 parts calibratorsolution to 98 parts control plasma, arriving at a final concentrationof the fluorogenic substrate of about 400 μM.

Samples of stents prepared according to this Example 1 (“test stents”)and of identical but bare-metal stents (“bare stents”) were prepared bycutting sections of each stent to a length of 9 mm. The 9 mm sections oftest stents and bare stents were placed individually in separate wellsof a black, opaque 96-well polystyrene microplate (Fisher Scientific,Waltham, Mass.). Test solution (330 microliters) was added to each wellcontaining a test stent or bare stent sample, as well as to severalwells each containing a 4 mm glass sphere (Fisher Scientific, catalogno. 11-312B) to serve as a positive control, and to several empty wellsto serve as a “blank” or negative control. Calibration mixture (330microliters) was added to several empty wells (separate from thenegative-control wells) to provide a calibration reference. Fluorescencewas measured in a Fluoroskan ASCENT' microplate reader (FisherScientific, catalog no. 5210470) with an excitation wavelength of 360nm, emission wavelength of 460 nm, reading interval of 20 to 30 seconds,and total experimental time of 150 minutes.

The test stents were found to result in a significant delay in peakthrombin formation, as compared to the bare stents. In particular, theelapsed time before peak thrombin formation was found to be about 4times the time observed with the bare stents (109.3 minutes for the teststents compared to 29.4 minutes for the bare stents). The test stentswere also found to result in a longer lag phase, i.e., the elapsed timebefore the onset of thrombin formation; the observed lag phase for thetest stents was about 4 times as long as that of the bare stents (99.3minutes for the test stents compared to 26.2 minutes for the barestents). The test stents were also found to result in lower peakthrombin concentration than the bare stents; the observed peak thrombinconcentration for the test stents was about 0.3 times that of the barestents (150.3 nM for the test stents compared to 473.6 nM for the barestents).

The test stents were also found to be only slightly more thrombogenicthan the empty (blank) polystyrene wells. In particular, the elapsedtime before peak thrombin formation of the test stents was found to beabout 97% of that measured for the empty wells (109.3 minutes for thetest stents compared to 112.3 minutes for the empty wells). The observedlag phase for the test stents was about 97% of that of the empty wells(99.3 minutes for the test stents compared to 102.9 minutes for theempty wells). The test stents were also found to result in a peakthrombin concentration that was only about 6% higher than that of theempty wells (150.3 nM for the test stents compared to 141.9 nM for theempty wells).

The thickness of the silane layer applied to the cobalt-chromiumfilaments was measured to be from about 1 to about 10 nanometers, andthe thickness of the MPC layer applied to the platinum-tungstenfilaments, and to the cobalt-chromium filaments over the silane layer,was measured to be from about 2 to about 3 nanometers.

Methods of Treatment

As mentioned elsewhere herein, the present disclosure also includesmethods of treating a vascular condition, such as an aneurysm orintracranial aneurysm, with any of the embodiments of the stentsdisclosed herein. The low-thrombogenicity stents of the presentdisclosure can, in some embodiments, be deployed across the neck of ananeurysm and the flow-diverting properties employed to reduce blood flowbetween the aneurysm and the parent vessel, cause the blood inside theaneurysm to thrombose and lead to healing of the aneurysm.

Significantly, the low-thrombogenicity stents disclosed herein canfacilitate treatment of a large population of patients for whomflow-diverter therapy has not been previously possible. Such patientsare those who have previously suffered from a hemorrhagic aneurysm orwho have been diagnosed as being at risk for hemorrhage from an aneurysmin the intracranial arterial system. These patients cannot currently betreated with commercially available flow-diverting stents because thosestents are bare metal, braided stents whose implantation requires thepatient to take anti-platelet medication (typically aspirin and PLAVIX™(clopidogrel)) for a long period of time following implantation. Thepurpose of the anti-platelet medication is to counteract the tendency ofthe bare-metal stent to cause thrombus (blood clots) to form in thepatient's vasculature. However, for a patient who has suffered from oris at risk of intracranial hemorrhage, taking the anti-plateletmedication can cause, or put the patient at higher risk of, such ahemorrhage. Low-thrombogenicity flow-diverting stents, such as someembodiments of the stents disclosed herein, can make flow-divertertherapy possible for patients who cannot tolerate anti-plateletmedication because the reduced thrombogenicity can reduce or eliminatethe need for blood thinners.

In order to implant any of the stents disclosed herein, the stent can bemounted in a delivery system. Suitable delivery systems are disclosed inU.S. patent application Ser. No. 14/040,477, filed Sep. 27, 2013, titledDELIVERY OF MEDICAL DEVICES; U.S. Patent Application Publication No.2013/0226276, published Aug. 29, 2013, titled METHODS AND APPARATUS FORLUMINAL STENTING; and in U.S. Pat. No. 8,273,101, issued Sep. 25, 2012,titled SYSTEM AND METHOD FOR DELIVERING AND DEPLOYING AN OCCLUDINGDEVICE WITHIN A VESSEL. The entire disclosures of both of thesedocuments are incorporated by reference herein and made a part of thisspecification. In particular, these documents' teachings regarding stentdelivery systems and methods may be employed to deliver any of thestents disclosed herein in the same manner, to the same bodilylocation(s), and using the same components as are disclosed in theseincorporated documents.

Generally, the delivery system can include an elongate core assemblyhaving a distal segment that supports or contains the stent, and bothcomponents can be slidably received in a lumen of a microcatheter orother elongate sheath for delivery to any region to which the distalopening of the microcatheter can be advanced. The core assembly isemployed to advance the stent through the microcatheter and out thedistal end of the microcatheter so that the stent is allowed toself-expand into place in the blood vessel, across an aneurysm or othertreatment location.

A treatment procedure can begin with obtaining percutaneous access tothe patient's arterial system, typically via a major blood vessel in aleg or arm. A guidewire can be placed through the percutaneous accesspoint and advanced to the treatment location, which can be in anintracranial artery. The microcatheter is then advanced over theguidewire to the treatment location and situated so that a distal openend of the catheter is adjacent to the treatment location. The guidewirecan then be withdrawn from the microcatheter and the core assembly,together with the stent mounted thereon or supported thereby, can beadvanced through the microcatheter and out the distal end thereof. Thestent can then self-expand into apposition with the inner wall of theblood vessel. Where an aneurysm is being treated, the stent is placedacross the neck of the aneurysm so that a sidewall of the stent (e.g. asection of the braided tube) separates the interior of the aneurysm fromthe lumen of the parent artery. Once the stent has been placed, the coreassembly and microcatheter are removed from the patient. The stentsidewall can now perform a flow-diverting function on the aneurysm,thrombosing the blood in the aneurysm and leading to healing of theaneurysm.

Because of the low-thrombogenic properties of the stents disclosedherein, certain additional aspects of the methods of treatment arepossible. For example, the patient can be one who has previouslysuffered from, or who has been diagnosed as being at risk of, hemorrhagefrom an aneurysm in arterial anatomy such as the intracranial arterialsystem. The patient may have been diagnosed as being at risk for anintracranial hemorrhage, a cerebral hemorrhage from an aneurysm, etc.The patient can be prescribed a reduced regimen of anti-plateletmedication as compared to the regimen or protocol that would benecessary for a patient who received an otherwise similar stent thatlacked the phosphorylcholine outer layer or surface. The regimen can be“reduced” in the sense that the patient takes a lower dosage, fewermedications, less powerful medications, follows a lower dosagefrequency, and/or takes medication for a shorter period of timefollowing implantation of the stent, or otherwise. Alternatively, thepatient may be prescribed no blood thinning medication at all.

The devices and methods discussed herein are not limited to theapplication of layers on stents, but may include any number of otherimplantable devices. Treatment sites may include blood vessels and areasor regions of the body such as organ bodies.

Although the detailed description contains many specifics, these shouldnot be construed as limiting the scope of the subject technology butmerely as illustrating different examples and aspects of the subjecttechnology. It should be appreciated that the scope of the subjecttechnology includes other embodiments not discussed in detail above.Various other modifications, changes and variations may be made in thearrangement, operation and details of the method and apparatus of thesubject technology disclosed herein without departing from the scope ofthe present disclosure. Unless otherwise expressed, reference to anelement in the singular is not intended to mean “one and only one”unless explicitly stated, but rather is meant to mean “one or more.” Inaddition, it is not necessary for a device or method to address everyproblem that is solvable by different embodiments of the disclosure inorder to be encompassed within the scope of the disclosure.

What is claimed is:
 1. A medical device, comprising: a ventricularassist device (VAD) having a surface comprising an outermost layer ofphosphorylcholine, wherein the outermost layer of phosphorylcholine hasa thickness of less than 100 nanometers.
 2. The medical device of claim1, wherein the VAD comprises at least one of steel, aluminum, titanium,cobalt, chromium, platinum, nickel, alloys thereof, or combinationsthereof.
 3. The medical device of claim 1, wherein the phosphorylcholineis selected from the group consisting of 2-methacryloyloxyethylphosphorylcholine, 2-acryloyloxyethyl phosphorylcholine, andphosphorylcholines based upon monomers including2-(meth)acryloyloxyethyl-2′-(trimethylammonio)ethyl phosphate,3-(meth)acryloyloxypropyl-2′-(trimethylammonio)ethyl phosphate,4-(meth)acryloyloxybutyl-2′-(trimethylammonio)ethyl phosphate,5-(meth)acryloyloxypentyl-2′-(trimethylammonio)ethyl phosphate,6-(meth)acryloyloxyhexyl-2′-(trimethylammonio)ethyl phosphate,2-(meth)acryloyloxyethyl-2′-(triethylammonio)ethyl phosphate,2-(meth)acryloyloxyethyl-2′-(tripropylammonio)ethyl phosphate,2-(meth)acryloyloxyethyl-2′-(tributylammonio)ethyl phosphate,2-(meth)acryloyloxypropyl-2′-(trimethylammonio)ethyl phosphate,2-(meth)acryloyloxybutyl-2′-(trimethylammonio)ethyl phosphate,2-(meth)acryloyloxypentyl-2′-(trimethylammonio)ethyl phosphate,2-(meth)acryloyloxyhexyl-2′-(trimethylammonio)ethyl phosphate,2-(meth)acryloyloxyethyl-3′-(trimethylammonio)propyl phosphate,3-(meth)acryloyloxypropyl-3′-(trimethylammonio)propyl phosphate,4-(meth)acryloyloxybutyl-3′-(trimethylammonio)propyl phosphate,5-(meth)acryloyloxypentyl-3′-(trimethylammonio)propyl phosphate,6-(meth)acryloyloxyhexyl-3′-(trimethylammonio)propyl phosphate,2-(meth)acryloyloxyethyl-4′-(trimethylammonio)butyl phosphate,3-(meth)acryloyloxypropyl-4′-(trimethylammonio)butyl phosphate,4-(meth)acryloyloxybutyl-4′-(trimethylammonio)butyl phosphate,5-(meth)acryloyloxypentyl-4′-(trimethylammonio)butyl phosphate,6-(meth)acryloyloxyhexyl-4′-(trimethylammonio)butylphosphate, andcombinations thereof.
 4. The medical device of claim 1, wherein a firstportion of the surface of the VAD possesses the phosphorylcholinedirectly bonded to the first portion of the surface, and wherein asecond portion of the surface of the VAD, different from the firstportion, possesses a silane layer between the second portion of thesurface and the phosphorylcholine.
 5. The medical device of claim 4,wherein the phosphorylcholine, or a polymer or copolymer thereof, ischemically bonded directly to the first portion.
 6. The medical deviceof claim 4, wherein the phosphorylcholine, or a polymer or copolymerthereof, is chemically bonded to the silane layer on the second portion.7. The medical device of claim 4, wherein the silane layer comprises asilane is selected from the group consisting of3-glycidoxypropyltrimethoxysilane,2-(3,4-epoxycyclohexyl)ethyl-triethoxysilane,2-(3,4-epoxycyclohexyl)ethyl-trimethoxysilane,(3-glycidoxypropyl)trimethoxysilane, (3-glycidoxypropyl)triethoxysilane,5,6-epoxyhexyltriethoxysilane, (3-glycidoxypropyl)methyldiethoxysilane,(3-glycidoxypropyl)methyldimethoxysilane,(3-glycidoxypropyl)dimethylethoxysilane,3-isocyanatopropyltriethoxysilane,(isocyanatomethyl)methyldimethoxysilane,3-isocyanatopropyltrimethoxysilane,tris(3-trimethoxysilylpropyl)isocyanurate,(3-triethoxysilylpropyl)-t-butylcarbamate,triethoxysilylpropylethylcarbamate, 3-thiocyanatopropyltriethoxysilane,and combinations thereof.
 8. The medical device of claim 4, wherein thesilane layer comprises 3-glycidoxypropyltrimethoxysilane.
 9. The medicaldevice of claim 1, wherein the phosphorylcholine comprises a copolymerhaving a reactive chemical group selected from the group consisting ofamine, hydroxyl, epoxy, silane, aldehyde, carboxylate and thiol.
 10. Themedical device of claim 1, wherein the VAD is less thrombogenic than anidentical device that does not comprise the outermost layer ofphosphorylcholine.
 11. The medical device of claim 1, wherein theoutermost layer of phosphorylcholine has a thickness from about 1 toabout 25 nanometers.
 12. The method of claim 1, wherein thephosphorylcholine comprises 2-methacryloyloxyethyl phosphorylcholine(MPC).
 13. A method comprising: applying a phosphorylcholine material toa surface of a ventricular assist device (VAD) to form an outermostlayer on the VAD, wherein the phosphorylcholine material has a thicknessof less than 100 nanometers.
 14. The method of claim 13, wherein the VADcomprises at least one of titanium, cobalt, chromium, platinum, nickel,alloys thereof, or combinations thereof.
 15. The method of claim 13,wherein applying the phosphorylcholine material to the surface of theVAD further comprises immersing the VAD in a phosphorylcholine solution.16. The method of claim 13, wherein the phosphorylcholine material isselected from the group consisting of 2-methacryloyloxyethylphosphorylcholine, 2-acryloyloxyethyl phosphorylcholine, andphosphorylcholines based upon monomers including2-(meth)acryloyloxyethyl-2′-(trimethylammonio)ethyl phosphate,3-(meth)acryloyloxypropyl-2′-(trimethylammonio)ethyl phosphate,4-(meth)acryloyloxybutyl-2′-(trimethylammonio)ethyl phosphate,5-(meth)acryloyloxypentyl-2′-(trimethylammonio)ethyl phosphate,6-(meth)acryloyloxyhexyl-2′-(trimethylammonio)ethyl phosphate,2-(meth)acryloyloxyethyl-2′-(triethylammonio)ethyl phosphate,2-(meth)acryloyloxyethyl-2′-(tripropylammonio) ethyl phosphate,2-(meth)acryloyloxyethyl-2′-(tributylammonio)ethyl phosphate,2-(meth)acryloyloxypropyl-2′-(trimethylammonio)ethyl phosphate,2-(meth)acryloyloxybutyl-2′-(trimethylammonio)ethyl phosphate,2-(meth)acryloyloxypentyl-2′-(trimethylammonio)ethyl phosphate,2-(meth)acryloyloxyhexyl-2′-(trimethylammonio)ethyl phosphate,2-(meth)acryloyloxyethyl-3′-(trimethylammonio)propyl phosphate,3-(meth)acryloyloxypropyl-3′-(trimethylammonio)propyl phosphate,4-(meth)acryloyloxybutyl-3′-(trimethylammonio)propyl phosphate,5-(meth)acryloyloxypentyl-3′-(trimethylammonio)propyl phosphate,6-(meth)acryloyloxyhexyl-3′-(trimethylammonio)propyl phosphate,2-(meth)acryloyloxyethyl-4′-(trimethylammonio)butyl phosphate,3-(meth)acryloyloxypropyl-4′-(trimethylammonio)butyl phosphate,4-(meth)acryloyloxybutyl-4′-(trimethylammonio)butyl phosphate,5-(meth)acryloyloxypentyl-4′-(trimethylammonio)butyl phosphate,6-(meth)acryloyloxyhexyl-4′-(trimethylammonio)butylphosphate, andcombinations thereof.
 17. The method of claim 13, wherein applying thephosphorylcholine material to the VAD further comprises: chemicallybonding the phosphorylcholine material directly on at least a firstportion of the surface of the VAD; applying a silane layer on a secondportion of the surface of the VAD, different than the first portion; andapplying the phosphorylcholine material on the silane layer on thesecond portion.
 18. The method of claim 17, wherein applying the silanelayer on the surface of the VAD further comprises immersing the VAD in asilane solution.
 19. The method of claim 17, wherein the silane layercomprises a silane selected from the group consisting of3-glycidoxypropyltrimethoxysilane,2-(3,4-epoxycyclohexyl)ethyltriethoxysilane,2-(3,4-epoxycyclohexyl)ethyl-trimethoxysilane,(3-glycidoxypropyl)trimethoxysilane, (3-glycidoxypropyl)triethoxysilane,5,6-epoxyhexyltriethoxysilane, (3-glycidoxypropyl)methyldiethoxysilane,(3-glycidoxypropyl)methyldimethoxysilane,(3-glycidoxypropyl)dimethylethoxysilane,3-isocyanatopropyltriethoxysilane,(isocyanatomethyl)methyldimethoxysilane,3-isocyanatopropyltrimethoxysilane,tris(3-trimethoxysilylpropyl)isocyanurate,(3-triethoxysilylpropyl)-t-butylcarbamate,triethoxysilylpropylethylcarbamate, 3-thiocyanatopropyltriethoxysilane,and combinations thereof.
 20. The method of claim 17, wherein the silanelayer comprises 3-glycidoxypropyltrimethoxysilane.
 21. The method ofclaim 17, wherein the silane layer has a thickness of less than 10nanometers.
 22. The method of claim 17, further comprising, prior toapplying the silane layer or the phosphorylcholine material,hydroxylating at least a portion of the surface of the VAD.
 23. Themethod of claim 13, wherein the phosphorylcholine material comprises acopolymer having a reactive chemical group selected from the groupconsisting of amine, hydroxyl, epoxy, silane, aldehyde, carboxylate,thiol, and combinations thereof.
 24. The method of claim 13, wherein thephosphorylcholine material defines a thickness of the outermost layerfrom about 1 nanometer to about 25 nanometers.
 25. The method of claim13, wherein the phosphorylcholine material comprises2-methacryloyloxyethyl phosphorylcholine (MPC).